Acquisition of CCDC88A/GIV through Tumor-Stroma Tunnels Promotes Aggressive Phenotypes of Estrogen Receptor-Positive Breast Cancer [dataset3]

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states. Co-culture model of bone marrow mesenchymal stem cells (MSCs)(HS5 and HS27a) and breast cancer cells (T47D). Co-cultured cancer and stromal cells were separated before performing RNA sequencing. Data sets also include monoculture samples of cancer and stromal cells as well as cancer cells with conditioned medium from stromal cells.